Osteoporosis is a common disease in post-menopausal women, related to estrogen deficiency and aging. Similarly there is increasing recognition that osteoporosis is also a significant problem in men. In this regard we have recently evalauated a group of middle aged men with idiopathic osteoporosis. These men were found to have reduced serum levels of insulin like growth factor I(IGF-I) which correlated with their reduced bone density. Over the past five years, we have become increasingly aware that osteoporosis may also develop in young women who are premenopausal with regular normal menses. The majority of such women have diseases that are associated with bone loss (primary or secondary hyperparathyroidism, hyperthyroidism, Cushing's disease, intestinal malabsorption, insulin dependent diabetes mellitus) or have been exposed to certain medications (glucocorticoids, anticonvulsants, cancer chemotherapeutic agents and possibly high doses of thyroxine) that cause bone loss. We have recently observed, however, that 18% (21) of a group of 117 younger women (less than 55) who presented to the Metabolic Bone Disease Unit with low bone mass have no definable cause of bone loss. These women tended to have a history of fractures. In addition, they frequently had a positive family history of osteoporosis, suggesting that their disease may have a genetic basis. The purpose of this proposal is to improve our understanding of the causes of low bone mass in premenopausal and perimenopausal women. We plan to conduct a thorough evaluation for secondary causes of bone loss, characterize biochemical markers of bone and mineral metabolism, and analyze other factors associated with bone mass, including serum levels of IGF-I and its binding proteins. In addition, we will also define polymorphisms of the following genes related to bone mass: IGF-I, aromatase and the vitamin D receptor.